The studies that make up this project have several related objectives. These include; 1) an understanding of the specific acute and chronic cognitive effects of alcohol; 2) the use of drug probes and models to provide a complimentary view of the determinants of learning and remembering from that available from brain imaging techniques; 3) the development of pharmacological models of impaired cognition as expressed in differnent neuropsychiatric disorders; 4) uncovering cognitive deficits in alcoholics that might ordinarily not be readily only apparent but would be expressed under drug challenge conditions. To meet these objectives both normal volunteers, alcoholics and other neuropsychiatric disorder patients are studied in repeated measures cross-over designs using several contrasting classes of drugs including benzodiazepines, serotinergic drugs, drugs that affect the cholinergic nervous system, drugs that interact with the NMDA receptor. Previously validated cognitive neuroscience methods are used to assess and contrast the cognitive effects of these agents in different populations of patients. Detoxified alcoholics, treated with benzodizepines (which mimics many of the effects of alcohol in the alcoholic), demonstrate a dramatic impairment in reflective cognitive functioning and inhibitory functions. This form of impairment is not nearly as apparent under placebo test conditions and furthermore this deficit is not secondary to changes in many other cognitive domains such as those involved in learning and remembering. In addition, access to what is in knowledge memory is qualitative different under benzodiazipine test conditions (compared to placebo) and this is not the case in normal volunteers. These findings provide some new perspective, in cognitive terms, some of the ways that alcohol alters mental functions in alcoholics that is distinguishable from the effects of alcohol in normals. As such it has important clinical implications. Parallel studies have explored the role of awareness in memory using benzodiazepines as a tool for altering cognitive functioning. Other studies have been designed to examine whether only some aspects of attentional functioning are impaired following alcohol administration in normal while other facets of attention are spared. This research has the dual goal of utilizing drug probes for exploring the differentiated nature of attention (as well as learning and memory) while at the same time providing new, and clinically relevant, information about the cognitive effects of alcohol. These attentional-cognitive studies are designed to contrast the effects of alcohol on goal-directed (or top-down) control processes with stimulus-driven (or bottom-up) control functions. Top-down cognitive functions are the types of operations that impaired in alcoholics. We have also demonstrated that the effects of other psychoactive agents such as drugs that effect the NMDA receptor mimic the cognitive changes expressed in normal aging but not that of amnesia or dementia in both young and elderly normal volunteers. Ketamine also potentiates the cognitive response to both benzodiazepines and cholinergic antagonists (such as scopolamine). In general the cognitive effects of each of these classes of drugs are largely independent of their sedative effects. In a study of early and middle stage Alzheimer's disease patients we were unable to demonstrate positive cognitive effects of stimulant treatments despite successful behavioral activation in these patients. This confirms previous findings from our laboratory demonstrating a dissociation between mood and stimulant effects of several drugs and their cognitive effects (including effects on learning, memory, attention and perception). Significance to Biomedical research: The findings have provided us with a clearer picture of the a) the specific cognitive deficits that are apparent in alcoholics and b) the impact of drugs that are similar to alcohol on the cognitive functioning of the alcoholic. These findings are important in understanding the mechanisms that account for normal memory as well as forms of impaired memory functions. This research also serves as a basis for the development of drug and behavioral treatments of cognitively impaired patients, particularly those suffering from addictions to alcohol and other psychoactive drugs.